Protein aggregation diseases or amyloid degeneration is a heterogeneous group of clinical states which have in common the criterion of, in many cases but not exclusively, a protein specific to each case being deposited extracellularly (systemically or locally) in the ordered conformation of a beta sheet structure. The group of protein aggregation diseases or protein misfolding diseases also includes Alzheimer's disease. Alzheimer's disease (in Latin: Morbus Alzheimer) in its most common form occurs in persons over the age of 65 as a neurodegenerative disorder. The pathogenesis thereof is characterized by an impairment of cognitive ability, which is usually accompanied by a decline in daily activities, with behavioral disorders and neuropsychological symptoms. The patients at an advanced stage forget long-known skills and no longer recognize people to whom they are close. Life expectancy after diagnosis of Alzheimer's disease is, from a statistical perspective, on average about seven to ten years.
Ferri et al. (Lancet. 366, No. 9503, 2005, pp. 2112-7) describe that in 2005, about 24 million people suffered from dementia, of which about 60% could be attributed to Alzheimer's disease). Alzheimer's disease is currently the most common form of dementia for which no causal therapy at present exists.
A pathological sign of Alzheimer's disease, which can be determined even before the first clinical symptoms, is provided by plaques (known as Alzheimer's fibrils). These protein aggregates consist largely of incorrectly folded amyloid beta peptide (also known as Abeta peptide or amyloid beta peptide) and are deposited in the brain of Alzheimer's patients (as described by Walsh and Selkoe: Journal of Neurochemistry 101: pp 1172-1184 (2007)) and are the result of an increased clustering of the amyloid beta peptide in the brain. The amyloid beta peptide fibrils are, however, only the final stage of a process which begins with the cleavage of monomeric amyloid beta peptide from APP (amyloid precursor protein), continues with the formation of neurotoxic amyloid beta peptide oligomers, and only then ends with amyloid beta peptide fibrils.
In order to prevent the clustering with the amyloid beta peptide, there are experimental therapies of active and passive immunization with the amyloid beta peptide fragment as an immunogen.
Experimental therapies are carried out in in vitro models of amyloid beta peptide aggregation, in cell models of amyloid beta peptide production, and also in transgenic mouse models which form amyloid beta peptide aggregates in the brain. More particularly, active and passive immunization as a therapy were carried out in the transgenic mouse model of amyloid beta peptide aggregation (as described by Schenk et al.: Nature (1999) and by Bard et al. (2003)). In the first description of active immunization, full-length L-amyloid beta peptide was used as an immunogen and resulted in clearance of the plaques in a mouse model of Alzheimer's disease in the context of an immunization (as described by Schenk et al., Nature (1999)). In a similar mouse model, passive immunization was also successfully applied. It became apparent that N-terminal epitopes in the region of amyloid beta peptide 1-11 were especially efficient in giving rise to cerebral clearance of the amyloid beta peptide fibrils (as described by Bard et al.: PNAS 100(4), pp 2023-2028 (2003)). Currently, two studies of passive immunization, for example, antibodies/antibody fragments, in patients with Alzheimer's disease are taking place (as described by Brody and Holtzman: Annual Reviews in Neuroscience 31, pp 175-193 (2008)).
Immunization was tested with success in animal experiments, but active immunization in humans resulted in a T cell-mediated autoimmune response or autoimmune disease, in which the endogenous immune system caused meningoencephalitis in the brain of the patient (as described by Brody and Holtzman: Annual Reviews in Neuroscience 31, pp 175-193 (2008)). Active immunization with the amyloid beta peptide fragment is therefore currently considered not to be promising.
Antibodies to the amyloid beta peptide for passive immunotherapy have been described by Bard et al. (PNAS 100(4), pp 2023-2028), by Dodel et al. (Ann Neurol 52, pp 253-256 (2002)), and in 2007 by Gardberg et al. (PNAS 104(40), pp 15659-15664 (2007)) to amino acids 1-8 of the amyloid beta peptide.
The immunization of old beagles with complete (1-42) fibrillar amyloid beta peptide has, for example, also been described by Head et al. (The Journal of Neuroscience 28(14), pp 3555-3566 (2008)). Differences between dogs and humans with respect to the use of the amyloid beta peptide as an immunogen exist, however, since, compared with humans, dogs show no counteractive autoimmune response.
Cribbs et al. (The Journal of Biological Chemistry 272(11), pp 7431-7436 (1997)) described the mechanism of the amyloid beta peptide and used the D- and L-isomers of the complete amyloid beta peptide and also a truncated form (amino acids 1-42 or 25-35). The stereospecificity was likewise described by Esler et al. The detection of proteins having an altered conformation/prions by using sequences which correspond to the target protein to be detected was described in US 2008/0171341 A1.
WO 02/081505 A2 describes the implementation of a phage display for identifying amino acid sequences which bind to the Ass peptide. U.S. Pat. No. 6,689,752 B2 describes the influence of sequences consisting of 3-5 amino acids on the aggregation of amyloid beta peptide.
Cribbs et al. described that neurotoxicity is not stereoisomer-specific. No tests for an immune response were, however, made, but reference was made to the lower immunogenicity of the D-isomers.
Geylis et al. described cell lines obtained from healthy human subjects which synthesize antibodies which bind to amino acids 1-16 of the amyloid beta peptide and the use thereof in passive immunization. Lee et al. (American Neurological Association 58, pp 430-435 (2005)) described the antibody sera from human subjects who did or did not develop meningoencephalitis after amyloid beta peptide immunization. A result of this investigation was that the antibodies were mainly directed against amino acids 1-8 of the amyloid beta peptide.